Three-dimensional polymer gel networks have been widely studied for use as delivery vehicles for a variety of solutes most particularly biologically active solutes.
Many methods of loading gels with solutes are presently available. Two of them relevant to drug loading include: (i) formation of the hydrogel in the presence of the solute (e.g., drug); and (ii) swelling of a preformed gel in a concentrated solution of the solute (e.g., drug). See, for example, Kim et al., Phar. Res. 9:283-289 (1992). Maximum loadings of high molecular weight solutes are generally on the order of about a few percent by weight of gel. Each of these techniques has serious limitations. In the first method, side reactions are possible between moieties reacting to form the hydrogel and the drug and it is often not possible to remove extractable materials from the gel after its formation without also extracting the drug. In the second method, solubility limitations become a drawback. That is, many drugs are sparingly soluble in water, and drug loading must be accomplished in non-aqueous solvents or water/solvent solutions. Since most naturally-occurring proteins, and proteins obtained from recombinant DNA techniques, are denatured or otherwise inactivated in non-aqueous solvents, this second method is not suitable for loading many biologically active materials. Moreover, large molecular weight materials (e.g., polypeptides) may be physically excluded from the hydrogels.
Partial denaturation of solutes such as vitamins, enzymes and the like is sometimes tolerated in purification/separation procedures since various methods have been developed to renature, or at least, reactivate the biologically active solute(s) once it has been purified. See, for example, Knuth and Burgess, "Purification of Proteins in the Denatured State", Protein Purification: Micro to Macro, pp. 279-305, Alan R. Liss, Inc., 1987. In separation/purification procedures protection of a particular solute (e.g., isolated enzyme, protein, vitamin) from inactivation during purification/separation procedure is preferred. In the drug delivery arts, it is counterproductive to even partially denature a biologically active solute once it is disposed on, or in, a delivery device since the solute must function when released.
Gref et al., Science, 263:1600-1602 (1994) have developed biodegradable nanospheres using amphiphilic co-polymers that phase-separate during emulsification. Loadings up to 45 percent by weight of a biologically active solute were achieved by dissolving the solute in the same organic solvent that dissolved the copolymer. Although loading is high using this method, the solute must be dissolved in a possible denaturant, i.e., an organic solvent.
Significantly, high loadings may lead to deactivation in other ways. For example, it is known that high levels of insulin are often used for insulin implants and controlled release devices. Reactions between the insulin molecules that are at high concentration lead to agglomeration and subsequent denaturation of the insulin. Furthermore, the manufacture of gel-based delivery devices will often require a drying step if the loaded gels are to be stored in their dry state between manufacture and use. Denaturation of the biologically active solute can also occur as a result of drying the gel.
What is required is a device and a method for loading effective amounts of solutes into polymer gel networks and that also avoid problems associated with denaturation or inactivation of the solute during, and after loading.